Since December 2019, the world was going to tackle a very contagious coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first emerged in Wuhan, China, and then rapidly outbreaks around the world. The infectious disease caused by this newly recognized species of coronavirus called the coronavirus disease 2019 (COVID-19)  SARS-CoV-2, with a typical crown-like shape, belongs to thefamily of single-stranded RNA viruses (+ssRNA). To date, seven coronaviruses have been identified that infect humans, including the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERSCoV), cause widespread epidemics in the last two decades. There is a 79.5% genetic similarity between SARS-CoV and SARSCoV- 2 . The main clinical manifestations of COVID-19 are fever, dry cough, fatigue, and muscle pain. Moreover, in severe cases, acute respiratory distress syndrome (ARDS) and multiple organ dysfunctions are among the life-threatening complications . In addition, robust findings so far showed that viruses could invade the CNS and cause severe damages to its structure and function. Viral infections can be responsible for encephalitis, toxic encephalopathy, and demyelinating lesions in infected patients . In this respect, increasing evidence shows that besides respiratory distress, neurological manifestations involved CNS, PNS, and skeletal muscles developed in 36.4% (78/214) of patients with COVID-19. Also, it has been reported that severe patients are more susceptible to develop neurologic symptoms . Nevertheless, this is not an unpredictable finding before these neurological manifestations have been observed in the infected patient with other coronaviruses such as in SARSCoV and MERS-CoV. For instance, autopsy studies confirm the presence of the SARS-CoV nucleic acid in the brain tissue and cerebrospinal fluid of those patients [6,7].
Similar to SARS-CoV, SARS-CoV-2 could induce neurological disorders such as hyposmia, weakness, headaches, altered consciousness, encephalitis, neuropathy, demyelination, and stroke [8,9]. Detection of the SARS-CoV-2 genome in cerebrospinal fluid of COVID-19 infected patients confirms this theory that SARS-CoV-2 can damage the nervous system . Viruses cause brain damages through diverse mechanisms that range from direct invasion to the brain or triggered indirect mechanisms such as the ‘Trojan horse’ mechanism (infected immune-functioning cells that cross the BBB by diapedesis) and coagulation cascade disruption [11-12].
Clinicians need to know how COVID-19 infection affects the nervous system. Thus, this review aimed to discuss the possible mechanisms by which SARS-CoV-2 causes cerebrovascular disease and stroke.
Direct Neuroinvasive Potential of SARS-CoV-2
Detection of the genetic material and also proteins of some viruses in cerebrospinal fluid or brain tissue specimens of some patients approves this theory that viruses can directly invade the nervous system and lead to nerve damage [13,14]. Angiotensinconverting enzyme 2 (ACE2), a cardio-cerebral vascular protection factor, has been identified in various organs, such as skeletal muscles and nervous system is known as significant the cell-entry receptor for SARS-Cov-2 and other coronaviruses . Under normal conditions, this enzyme has a critical role in regulating blood pressure and anti-atherosclerosis mechanisms . Coronaviruses may, through binding to this receptor, increase blood pressure and the risk of cerebral hemorrhage. Expression of ACE2 on nerve cells and vascular endothelial cells may elucidate the direct entry of SARS-CoV-2 into the CNS through hematogenous spread or retrograde transport of virus through ACE2 receptor. However, a more recent study demonstrated the probable endothelial invasion of SARS-CoV-2 in the case with posterior reversible encephalopathy syndrome (PRES)-like leukoencephalopathy .
CNS is protected by the blood-brain barrier (BBB), and dysfunction of this barrier can lead to the penetration of viruses to the brain. Due to the unique biological properties of the CNS, if a virus enters the CNS, it is difficult to remove, which exacerbates neurological insults. Damage to BBB and attacking the vascular system is Another scenario for the direct entrance of SARS-CoV-2 into CNS .
Indirect Neuroinvasive Potential of SARS-CoV-2
Stroke is a serious health problem that threatens the life of millions of people all over the world. Virus infections, especially respiratory tract virus infections are among the risk factors that can trigger stroke. Moreover, seasonal variation in stroke incidence emphasis the role of respiratory tract virus infections such as influenza . A retrospective study conducted by Li Y et al. revealed that the incidence of stroke among hospitalized, COVID-19 infected patients was approximately 5% . Moreover, the study of Mao et al. showed that about 5.7% of patients with a severe infection of COVID-19 develop the late cerebrovascular disease . Most of these patients were severe cases of COVID-19 and had a higher incidence risk of underlying diseases like diabetes, hypertension, coronary artery disease, and previous cerebrovascular disease . Additionally, several case reports from different countries confirm these findings [22,23].
Moreover, a recent study reports five cases of large-vessel stroke in young patients with COVID-19 . This finding is following previous reports showed the association between large-vessel stroke and the 2004 SARS-CoV outbreak in Singapore . Moreover, a retrospective cohort study proposed the coagulopathy and vascular endothelial dysfunction as other complications of COVID-19 . Viruses through increasing the risks of cardioembolic and arterio-arterial embolic events may cause stroke in infected patients . A study demonstrated that 31% of ICU patients with COVID-19 infections develop thrombotic complications. These results proposed that COVID-19 may predispose thromboembolism due to hypoxia, excessive inflammation, immobilisation and diffuse intravascular coagulation . Therefore, disruption of coagulation cascade may trigger the indirect effects of SARS-CoV2, which results in unusual thrombosis or hemorrhage occurred in strokes and acute hemorrhagic necrotizing encephalopathy .
In another study, Tan et al. evaluated the activated partial thromboplastin time-based clot waveform analysis (CWA) in COVID-19 patients and concluded that the rise of CWA parameters precedes and coincides with the severity of disease and ICU admission . Radiologic and histopathologic evaluation of 16 patients with severe COVID-19 showed that these patients are faced with the risk for ischemic lesions and multifocal microvascular hemorrhagic in the subcortical and deep white matter .
Pieces of evidence from the experimental mouse model of influenza suggest that virus infection causes cytokine storm and subsequently aggravates stroke outcomes . Likewise, accumulating evidence suggests that coronaviruses, especially SARS-CoV-2, trigger cytokine cascade, and probably by this way, cause cerebrovascular damages [30,31]. On the otherhand, a severe reduction in platelet levels and an increase in D-dimer levels have been reported in severely SARS-CoV-2 infected patients, which may make prone these patients to acute cerebrovascular events . Elevated levels of D-dimer induced hypercoagulability and exaggerated inflammatory status, which might play a critical role in the pathophysiology of stroke in patients with COVID-19 infection . Mao et al.’s study reveals the correlation between the severity of COVID-19 infection and higher D-dimer levels in patients. Patients with severe infection and higher D-dimer levels were more likely to develop neurological symptoms (45.5% vs. 30.2%), particularly acute cerebrovascular disease (5.7% vs. 0.8%) . Association studies shed new light on the role of the immune system in mediating the effect of viral infection on the nervous system. Multiple organs failure, which is one of the main reasons for the high mortality of COVID-19, occurs due to virus-induced systemic inflammatory response syndrome . Moreover, SARS-CoV-2, like other coronaviruses, displays neurotropic properties and can invade nervous tissues and activate immune cells such as microglia, macrophages, and astrocytes in the CNS and cause chronic inflammation and brain damage . There are rare brain autopsies and pathology data, but lungs and kidney autopsy findings suggest thrombotic microangiopathy in these organs [35-37]. Solomon et al., by histopathological examination of brain samples of 18 died COVID-19 patients, only observed hypoxic changes and not encephalitis or other brain changes related to the virus. Also, the level of the virus was low in brain sections of 5 patients . Further brain autopsy studies are needed for the understanding of the neurological implications of COVID-19.
The COVID-19 causes various pathological conditions, such as ARDS, cardiovascular and cerebrovascular complications. However, the relation between COVID-19 and cerebrovascular diseases is not yet determined. Several important questions remain unknown about the pathophysiology of COVID-19 and stroke. SARS-CoV-2 can directly or indirectly tackle the nervous system described above, and healthcare professionals should be aware of these neurologic manifestations in COVID-19 patients. Numerous studies showed that patients with COVID-19 had elevated CRP, D-dimer, and platelet abnormalities, causing hyperactivation of inflammatory factors, damaged coagulation cascade. Notwithstanding the wealth of evidence supporting the possible mechanisms involved in the pathophysiology of stroke and COVID-19, further studies are needed to disclose the details.
The authors would like to express their sincere gratitude to the Imam Khomeini Hospital Research and Development Unit, Ahvaz Jundishapur University of Medical Sciences for the support of this study.
Conflict of Interest
The authors declare that there is no conflict of interest.